Novel anti-LAG-3 antibody LBL-007 with anti-PD-1 blockade enhances antitumor immunity by promoting T cell-induced apoptosis.

Immune checkpoint combination therapy, particularly dual LAG-3/PD-1 blockade, demonstrates superior clinical efficacy over monotherapy in cancers like melanoma, yet its mechanistic synergy requires further validation. In this study, we established a cell co-culture model by co-culturing LAG-3(+)PD-1(+) Jurkat cells induced by phytohemagglutinin (PHA) and human tumor cells with high expression of LAG-3 and PD-1 major ligands to characterize the combination effect of LBL-007 with anti-PD-1 antibodies and the mechanism of action in cancer immunotherapy. The results showed that the combination of LBL-007 and anti-PD-1 antibodies in the cell co-culture model enhanced the ability of activated Jurkat cells to kill tumor cells compared with monotherapy. Furthermore, this combination also inhibited the apoptosis of Jurkat cells and promoted IL-2, IL-10, and TNF secretion from Jurkat cells. Tumor cell death via apoptosis induced by activated Jurkat cells was observed, which was enhanced by combined LBL-007 and anti-PD-1 antibody treatment. The combination of LBL-007 and anti-PD-1 antibodies delayed tumor growth and promoted tumor cell apoptosis compared with monotherapy in human LAG-3 transgenic mice subjected to transplantation with colorectal tumor cells. Taken together, the combination of LBL-007 and anti-PD-1 antibodies plays an enhanced antitumor role by improving T cell viability and activity as well as by promoting T cell-induced apoptosis, thereby suggesting this combination as a potential effective strategy for cancer immunotherapy.